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Local anesthetics are used for performing various regional anesthesia techniques to provide intraoperative anesthesia and analgesia, as well as for the treatment of acute and chronic pain. Older medications such as lidocaine and bupivacaine as well as newer ones such as mepivacaine and ropivacaine are being used successfully for decades. Routes of administration include neuraxial, perineural, intravenous, various infiltrative approaches, topical, and transdermal. There are new innovations with the use of older local anesthetics in a novel manner, in addition to the development and use of new formulations. This chapter seeks to summarize the pharmacokinetics of local anesthetics and address the role of newer local anesthetics, as well as clinical implications, safety profiles, and the future of local anesthetic research. Finally, some clinical pearls are highlighted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Incubations were carried out with batch cultures of ruminal micro-organisms from sheep to analyse the influence of the N source on in vitro CH 4 production. The two substrates were mixtures of maize starch and cellulose in proportions of 75:25 and 25:75 (STAR and CEL substrates, respectively), and the three nitrogen (N) sources were ammonia (NH 4 Cl), casein (CA) and isolated soya bean protein (SP). Five isonitrogenous treatments were made by replacing non-protein-N (NPN) with CA or SP at levels of 0 (NPN), 50 (CA50 and SP50, respectively) and 100% (CA100 and SP100) of total N. All N treatments were applied at a rate of 35 mg of N/g of substrate organic matter and incubations lasted 16.5 h. With both proteins, N source × substrate interactions (p = 0.065 to 0.002) were detected for CH 4 production and CH 4 /total VFA ratio. The increases in CH 4 production observed by replacing the NPN with protein-N were higher (p < 0.05) for STAR than for CEL substrate, but the opposite was observed for the increases in volatile fatty acid (VFA) production. As a consequence, replacing the NPN by increased levels of CA or SP led to linear increases (p < 0.05) in CH 4 /total VFA ratio with STAR, whereas CH 4 /total VFA ratio tended (p < 0.10) to be decreased with CEL substrate. Increasing the amount of both proteins decreased linearly (p < 0.05) ammonia-N concentrations, which may indicate an incorporation of amino acids and peptides into microbial protein without being first deaminated into ammonia-N. In incubations with the tested N sources as the only substrate, the fermentation of 1 mg of CA or SP produced 1.24 and 0.60 μmol of CH 4 respectively. The results indicate the generation of CH 4 from protein fermentation, and that the response of CH 4 production to protein-N supply may differ with the basal substrate., (Journal of Animal Physiology and Animal Nutrition © 2017 Blackwell Verlag GmbH.)

Background: The goal of this in vitro study was to investigate the effects of lipid emulsion (LE) on local anesthetic levobupivacaine-induced responses in isolated rat aorta and to determine whether the effect of LE is related to the lipid solubility of local anesthetics., Methods: Isolated rat aortic rings were suspended for isometric tension recording. The effects of LE were determined during levobupivacaine-, ropivacaine-, and mepivacaine-induced responses. Endothelial nitric oxide synthase and caveolin-1 phosphorylation was measured in human umbilical vein endothelial cells treated with levobupivacaine alone and with the addition of LE., Results: Levobupivacaine produced vasoconstriction at lower, and vasodilation at higher, concentrations, and both were significantly reversed by treatment with LE. Levobupivacaine and ropivacaine inhibited the high potassium chloride-mediated contraction, which was restored by LE. The magnitude of LE-mediated reversal was greater with levobupivacaine treatment than with ropivacaine, whereas this reversal was not observed in mepivacaine-induced responses. In LE-pretreated rings, low-dose levobupivacaine- and ropivacaine-induced contraction was attenuated, whereas low-dose mepivacaine-induced contraction was not significantly altered. Treatment with LE also inhibited the phosphorylation of endothelial nitric oxide synthase induced by levobupivacaine in human umbilical vein endothelial cells., Conclusions: These results indicate that reversal of levobupivacaine-induced vasodilation by LE is mediated mainly through the attenuation of levobupivacaine-mediated inhibition of L-type calcium channel-dependent contraction and, in part, by inhibition of levobupivacaine-induced nitric oxide release. LE-mediated reversal of responses induced by local anesthetics may be related to their lipid solubility.

Blood concentrations of tetracaine and its metabolite, p-butylaminobenzoic acid, were measured after spinal anesthesia with tetracaine which had been administered to patients under going orthopedic surgery. Tetracaine, an ester anesthetic, was given to 10 patients, the dose was 8-14mg, and blood samples were collected 1, 2 and 6h after the injection of tetracaine. We used gas chromatography/mass spectrometry for purposes of analysis. Tetracaine was not detected in any blood sample, but the metabolite was detected in each sample with the mean concentrations of 126.5, 97.9 and 43.3ng/ml at 1, 2 and 6h, respectively. This data will be useful in determination of the cause of death after spinal anesthesia with tetracaine.

Patients with drug allergy show a specific immune response to drugs. Chemically nonreactive drugs like, for example, local anesthetics are directly recognized by alphabeta+ T cells in an HLA-DR restricted way, as neither drug metabolism nor protein processing is required for T cell stimulation. In this study we identified some of the structural requirements that determine cross-reactivity of T cells to local anesthetics, with the aim to improve the molecular basis for the selection of alternatives in individuals sensitized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine specific, three mepivacaine specific from two allergic donors) were analyzed. Stimulatory compounds induced a down-regulation of the T cell receptor, demonstrating that these non-peptide antigens are recognized by the T cell receptor itself. A consistent cross-reactivity between lidocaine and mepivacaine was found, as all except one lidocaine specific clone proliferated to both drugs tested. Sixteen chemically related local anesthetics (including ester local anesthetics, OH- and desalkylated metabolites) were used to identify structural requirements for T cell recognition. Each of the four clones examined in detail was uniquely sensitive to changes in the structures of the local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all OH-metabolites and other differently modified molecules. The broadly reactive clone OFB2 allowed us to propose a model, suggesting that the structure of the amine side chain of local anesthetics is essential for recognition by the T cell receptor.

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperitoneally at 10:00, 16:00, 22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.

The mechanism of the prolonged effect of dextran on the duration of local anaesthesia has been studied. Using radio-active mepivacaine it was found that dextran prolonged the duration of infiltration anaesthesia in guinea-pigs by delaying the absorption of the local anaesthetic agent. Experiments in vitro indicate that molecular complexes between the local anaesthetic and dextran may be formed and it is assumed that the delayed absorption might be due to the formation of such molecular complexes. This hypothesis was strengthened by experiments in which dental infiltration anaesthesias were performed in healthy volunteers.

Pulmonary uptake of lidocaine was investigated in patients before surgery, and aimed at elucidating the influence of general anaesthesia, the presence of another local anaesthetic agent in the blood, or the possible impact of lung insufficiency. When the lung uptake of lidocaine, injected as a bolus together with indocyanine green dye, was calculated as uptake at 95% pass of the dye, there were no statistically significant differences between the four groups. When the extraction in each of the arterial blood samples was calculated on the basis of the relation between relative concentrations, there were statistically significant differences, with a general tendency towards higher extraction of lidocaine in the awake, healthy volunteers, not given mepivacaine, compared to the other groups. In the group in whom mepivacaine was infused, the arterial concentration of mepivacaine increased transiently after the injection of lidocaine. This probably reflects a displacement of mepivacaine from binding sites for both agents. From this study, it is postulated that the ability of the pulmonary circulation to clear the blood of lidocaine is high, and that it is not affected markedly by those situations studied in the present investigation.

Attempts have been made to correlate the duration of the local anesthetic effect with the amount of the local anesthetic compound remaining at the injection site at different times after an injection. In addition to delaying the absorption of the local anesthetic, adrenaline but not a vasopressin-derivate decreased the minimal anesthetic concentration of the local anesthetic agent. It is assumed that the pH value of the tissues at the injection site was kept down through the metabolic effects of adrenaline, thereby transforming the local anesthetic agent into cations, which is the form in which the amide-type of local anesthetics mainly exerts their nerve blocking activity.

In animals and humans the rate of resorption and the duration of the anesthesia have been investigated, using mepivacaine in different concentrations and volumes without addition of a vasoconstrictor. A linear relationship between duration of anesthesia and the logarithm to the concentration of mepivacaine was found.

Expected blood levels of common local anesthetics have been reported for numerous types of injections. Comparative levels of mepivacaine and lidocaine after dental injection have been only partially evaluated. A study was designed to compare the circulating serum level of 36 mgs. of mepivacaine with 1:20,000 levonordefrin (M) and 36 mgs. of lidocaine with 1:100,000 epinephrine (L) in 1.8 cc dental cartridges after standardized's bilateral maxillary infiltrations. Each of five subjects received 1.8 cc of (L) to the left maxillary second bicuspid and 1.8 cc of (M) to the right maxillary second bicuspid at a rate of one cc per minute. The serum was sampled before the injections and at 5, 15, 30, 60, 90, 120 and 240 minute intervals after the injections and analyzed by gas liquid chromatography. The results indicated that the serum level of (M) peaked at 30 minutes, 0.37 μg/ml of serum and (L) had peaks at 15 and 30 minutes, 0.22 μg/ml of serum. This difference was statistically significant, (p <.01) at all times sampled with (M) always resulting in a higher serum level. Serum levels persisted throughout the four hour test period.

(1) Amide local anaesthetics are almost completely metabolized before excretion in both animals and man. (2) Considerable interspecies variability occurs in the quantitative excretion of local anaesthetic metabolites; however, qualitative similarities often exist. (3) The secondary amine metabolite of lignocaine, MEGX, is capable of reacting in vivo with acetaldehyde, formed as a metabolite of ethyl alcohol, to produce a cyclic condensation product. (4) Although hydrolysis in man of the secondary amine metabolite of lignocaine, MEGX, appears extensive, the same is not true for the metabolic analogue produced from mepivacaine, PPX. (5) Metabolism of mepivacaine by the neonate is impaired, but the excretion process in the newborn is capable of eliminating the drug within 24 hr after birth. (6) Metabolic data on bupivacaine and etidocaine are incomplete. The latter compound appears to have a more rapid plasma clearance.

Local anaesthetic agents, both of the amide type (e.g., lidocaine, bupivacaine, etidocaine) and of the ester type (e.g., 2-chloroprocaine) are widely used to relieve pain in obstetric and gynaecological practice. The pharmacokinetics of these compounds are discussed in this review, with particular emphasis on the fetal exposure and its relationship to adverse effects on the fetus. 2-Chloroprocaine is rapidly hydrolyzed by esterases, and only traces of this compound reach the fetus, even following multiple injections, suggesting safety for the fetus. The main disadvantage of this compound is the short duration of action (0.5-1 h). The amide-type agents are active for longer time periods (up to several hours). The fetal/maternal total concentration ratios were approximately 0.3 for bupivacaine and etidocaine, 0.5 for lidocaine, 0.7 for mepivacaine, and 1 for prilocaine. The low ratios of bupivacaine and etidocaine result from extensive binding (90%) of these drugs to maternal alpha1-acid glycoprotein which exceeds corresponding fetal protein binding (50%). These low fetal/maternal total concentration ratios cannot be equated with fetal safety, because fetal side effects are better related to the free drug levels. Since the amide-type anaesthetics are weak bases, fetal acidosis will increase the maternal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects. Addition of epinephrine to the injection solution reduces the maternal blood levels of the amide-type compounds, but apparently not the fetal levels to the same extent. Because of possible unwanted effects of epinephrine (decreased uterine blood flow), the addition of this compound is not generally accepted to be of advantage. Paracervical blockade may result in elevated fetal blood levels (possibly by transarterial diffusion into uterine arteries) and possibly fetal bradycardia.

A very rapid resorption of the amide-type local anaesthetic agents most commonly used in obstetrics results in detectable plasma levels in mother and fetus within 5 to 10 minutes, respectively, after peridural anaesthesia. The various local anaesthetics differ from each other as far as their protein-binding capacity and the resulting ratios of umbilical vein to maternal blood levels are concerned. The feto-maternal ratio is inversely correlated to the degree of protein-binding. Both, the protein-binding capacity and the feto-maternal ratio do not indicate the total amount of the anaesthetic transferred across the placenta. In contrast to measurements of the plasma concentrations only the measurement of the anaesthetic in the fetal tissue would give an exact information about the fetal uptake of local anaesthetics. Several observations hint at the possibility that there are interactions between local anaesthetics and other drugs: A competitive displacement of local anaesthetics from their protein binding sites resulting in an increase in the unbound fraction is suggested. Since the feto-maternal equilibration exists only for the unbound fraction interactions of local anaesthetics with simultaneously administered drugs should be taken into consideration.

In the present investigation it is shown that administration of polyphloretin phosphate (PPP) together with local anaesthetics decreased the duration of infiltration anaesthesia in guinea-pigs. Furthermore, it is shown that in infiltration anaesthesias the local anaesthetic effect was terminated within a few minutes by administration of PPP. In experiments with high- and low-molecular fractions of PPP, the "anti-local anaesthetic" effect of PPP was not due to the antiprostaglandin activity of PPP. There was no effect of PPP on the duration of the nerve-blocking activity of mepivacaine in rats. Neither did the administration of PPP influence the toxic effects of mepivacaine in rabbits.

The tolerance and pharmacokinetic properties of mepivacaine and prilocaine were compared following i.v. infusion of 250 mg (0.88 and 0.97 mmol respectively) of each drug in five healthy volunteers. Side-effects were minor and occurred in only two subjects during the infusion of mepivacaine. Plasma concentrations of mepivacaine were greater in each subject than the corresponding values for prilocaine. The elimination half-life of mepivacaine was generally longer than that for prilocaine, whereas the total body clearance of prilocaine was consistently greater than the corresponding value for mepivacaine. For each subject the clearance of prilocaine substantially exceeded normal heptic blood flow and therefore an extra-hepatic site of metabolism of prilocaine has been postulated.

Because of the minimal effects on mother and fetus, regional anesthetic technics are widely employed for labor and delivery. However, the literature describes at least 35 fetal and neonatal deaths and a frightening incidence of fetal distress associated with paracervical block for 1st-stage labor. Continuous lumbar epidural anesthesia for 1st-stage labor has also been associated with fetal distress, but this is minimal and no deaths have been reported. Bupivacaine, a relatively new, long-lasting local anesthetic, is extemely toxic when administered paracervically, but no deaths have been reported with its use for epidural anesthesia. While choice of method and agent must be individualized, continuous lumbar epidural block with bupivacaine appears as effective as and less often dangerous to the fetus than paracervical block.

The present study has utilized a clinical model to compare the pharmacokinetics of four currently available amide local anaesthetic agents in theoretically equipotent concentrations. In addition to providing comparative data concerning the onset and duration of analgesia, anaesthesia, paresis, and paralysis, it has provided definitive confirmation of the clinical impression that under certain circumstances following the performance of a nerve block, motor blockade may actually precede sensory blockade, and an explanation for this seeming violation of established neurophysiological principles has been postulated. The study has also raised questions concerning the sequence of recovery from motor and sensory blockade which still await explanation.

Mepivacaine hydrochloride, 25 and 50 mg/kg sc (with sacrifice at 15 min) produced higher (p less than 0.005) drug levels in neonate (24--36-hr-old) rat brain and blood than in adult rat brain and blood; however, there was no significant difference in the brain-to-blood ratio of the drug between neonates and adults at either dose level. Intraarterial infusion of mepivacaine hydrochloride (20 micrograms/min) in adult rats resulted in measurable (GLC) mepivacaine base levels in pilocarpine-induced parotid salivary secretions collected throughout 30- and 45-min infusion periods. The saliva-to-blood ratios (+/- SEM) of mepivacaine base were 0.64 +/- 0.13 after a 30-min infusion and 2.13 +/- 0.48 after a 45-min infusion.

The introduction of the new long acting local anaesthetics, bupivacaine and etidocaine, has stimulated an expansion of interest in regional anaesthesia, particularly for obstetrical applications and pain therapy. System toxicity following injection of local anesthetics occurs albeit infrequently, and tentative correlations have been made between the onset of CNS and cardiovascular effects and circulating drug concentrations in both adults and neonates. Amongst other factors, interpretation of these relationships depends upon blood distribution and plasma binding of the agents, sampling sites and acid-base balance. The disposition kinetics and placental transfer of the amide type agents have been well characterised. In adults their clearance is almost entirely hepatic but in neonates an increase in the renal component is, in part, a reflection of the immaturity of some of the enzymes responsible for their metabolism. Ester type agents are rapidly hydrolysed by plasma pseudocholinesterase and this has led to a preference for chloroprocaine in some obstetric procedures. Major determinants of the systemic absorption of the agents after perineural administration include their physicochemical and vasoactive properties, perfusion and tissue binding at the site of injection and whether or not adrenaline has been added. In respect of blood drug concentrations achieved after various regional anaesthetic procedures, the margin of systemic safety appears to favour bupivacaine and etidocaine compared to shorter acting analogues such as lignocaine and mepivacaine. The time course of local anaesthetic remaining at the site of injection has been calculated following intravenous regional anaesthesia and peridural block. This has allowed prediction of the local and systemic accumulation of the drugs following contined dosage. Blood concentrations of local anaesthetics after perineural injection are not closely related to age, weight or pregnancy but may be influenced by diseases associated with haemodynamic changes and by other drugs given at or around the time of regional blockade.

To elucidate the mechanism of any drug displacement interaction, we examined the protein binding of mixtures of mepivacaine and bupivacaine in serum and solutions of albumin or alpha 1-acid glycoprotein. Protein binding data with mepivacaine alone were best described by a model with one class of binding site and a partitioning constant in serum and by a model with one class of binding site in both isolated protein solutions. Binding affinity of mepivacaine in serum was reduced in the presence of bupivacaine. Displacement of mepivacaine by bupivacaine was observed when an alpha 1-acid glycoprotein solution was studied. Classic competitive inhibition was demonstrated. Bupivacaine reduced mepivacaine binding to albumin, but the degree of displacement was not significant. When administered simultaneously, these two amino-amide local anesthetics interact synergistically to produce a higher than expected free concentration of mepivacaine. This interaction increases the risk of toxicity.

Information derived from measurements of blood concentrations of local anaesthetics can be extended by the application of pharmacokinetic anaylsis. A better understanding of quantitative aspects of the disposition and absorption of these drugs should assist the anaesthetist in deciding the optimal agent and dosage for regional block techniques.

Seven infants developed mepivacaine intoxication secondary to accidental injection during paracervical or pudental blocks or both. All presented with unexplained neonatal depression at birth, tonic seizures (often with apnea) within six hours, and characteristic neurologic findings. Twenty-four-hour urinary excretion produced 12.7 to 37.4 mg, exchange transfusions less than 1.02 to 3.5 mg, and gastric drainage or lavage or both 0.63 to 1.26 mg of mepivacaine. Thus promotion of urinary excretion is the treatment of choice. All six survivors are seizure free and neurologically and developmentally normal at one to 4 1/2 years. With early diagnosis and prevention of severe perinatal hypoxia, the prognosis from intoxication alone is very good.

The concentrations of lidocaine and mepivacaine were measured in stored cord blood samples from 200 deliveries. Newborn and obstetrical charts were reviewed for 100 deliveries for study of the association between cord blood concentrations, drug and route of recorded administration, Apgar scores at birth, and symptoms of possible toxicity. Detectable concentrations were commonly found (117/200), but toxic (3 micrograms/ml) levels were uncommon (4/200). However, recovery studies indicate these levels underestimate maximal exposure because both lidocaine and mepivacaine levels were shown to decrease in refrigerated stored blood. Although toxicity was seldom suspected, diagnostic accuracy was poor. The diagnosis was missed in the two patients with very high levels (5.0 and 9.0 micrograms/ml) of mepivacaine and levels measured in two suspected cases of toxicity were both low (0.4 microgram/ml). Associations between Apgar scores, cord levels, and route of administration (especially for lidocaine) were examined for 65 full-term uncomplicated deliveries. However, evaluation of these associations is problematic because dosages given, time or route of administration, and/or Apgar scores were often either not given or inconsistent with the clinical history. Detectable and potentially clinically significant local anesthetic drug concentrations were found in cord blood after all methods of administration, including local infiltration. These levels appear to underestimate the level of exposure because of instability of these anesthetics in stored cord blood samples. Local anesthetic toxicity appears to be difficult to detect clinically and may require cord blood level monitoring to detect.